Delivery system for omeprazole and its salts

Abstract

The present invention provides a time-release dosage form for delivering an acid-labile pharmaceutical, such as omeprazole, into the upper portion of the gastrointestinal tract downstream of the stomach. The dosage form includes a drug-containing core surrounded by an inert time-release coating that delays release of the drug from the core until expiration of a certain time period after administration, generally 0.5-5.0 hours or 1-3 hours. When the gastrointestinal fluid contacts the core, the drug is released rapidly into the GI tract. The dosage form does not contain an enteric coating. The dosage form can also include one or more additional coatings exterior to the time-release coating to provide delivery of an immediately released loading dose of the acid-labile drug or another drug.

What is claimed is:  
     
       1. A solid dosage form that provides a delayed and subsequently rapid release of omeprazole into an environment of use, wherein the dosage form comprises: 
       a core comprising omeprazole and at least one pharmaceutical excipient, wherein the core rapidly releases the omeprazole after the core is contacted with a fluid in an environment of use; and  
       a time-release non-enteric water soluble or water erodible coating surrounding and in contact with the core, wherein the coating delays the contact of the core with a fluid in an environment of use for a sufficient period of time to delay the release of the omeprazole from the core, and the coating loses its physical integrity in an essentially pH independent manner after the delay thereby permitting the core to rapidly release the omeprazole into the environment of use; and  
       wherein, the dosage form excludes an enteric release coating made from an enteric release polymer; the dosage form is adapted for oral administration; the time-release coating is sufficiently thick to retain its chemical and physical integrity in the stomach when administered orally; and the time-release coating loses its physical integrity in the upper portion of the GI tract downstream from the stomach thereby releasing omeprazole.  
     
     
       2. The solid dosage form of  claim 1 , wherein the dosage form is a granule, bead, pellet, tablet, agglomerate, crystal, spheroid, microsphere, seed, capsule, microcapsule, or mini-tablet. 
     
     
       3. The solid dosage form of  claim 2  wherein, the dosage form is a capsule containing plural granules, beads, pellets, agglomerates, crystals, spheroids, microspheres, seeds, microcapsules, or mini-tablets. 
     
     
       4. The solid dosage form of  claim 1 , wherein the core contains one or more osmotic agents that promote a buildup of osmotic pressure in the core following contact with water. 
     
     
       5. The solid dosage form of  claim 1 , wherein the core further comprises one or more alkaline reacting compounds. 
     
     
       6. The solid dosage form of  claim 1 , wherein the core further comprises a disintegrant. 
     
     
       7. The solid dosage form of  claim 1 , wherein the time-release coating comprises one or more hydrophilic or hydrophobic polymers or additives that regulate the strength, erosion property and/or diffusion property of the coating. 
     
     
       8. The solid dosage form of  claim 1 , wherein the time-release coating comprises one or more of an electrolyte, clay, polysaccharide and a hydrophilic material that influences the period of time it takes for the external aqueous medium to reach the pellet or tablet core containing the drug. 
     
     
       9. The solid dosage form of  claim 1 , wherein the time-release coating begins to erode shortly after administration to a patient and continues to erode for a period of at least 1 hour after which it loses its physical integrity and exposes the core to the environment of use thereby providing a delayed release of omeprazole. 
     
     
       10. The solid dosage form of  claim 1 , wherein the time-release coating does not erode initially, but permits the diffusion of an aqueous fluid therein and delays exposure of the core to the aqueous fluid for a period of at least 1 hour after which time the core rapidly disintegrates and the time-release coating loses its physical integrity. 
     
     
       11. The solid dosage form of  claim 1 , wherein the time-release coating is about 100-5000 microns thick and delays the release of omeprazole from the core at least about 1 hour after administration. 
     
     
       12. The solid dosage form of  claim 1 , wherein the time-release coating delays the release of omeprazole from the core for a period of about 1-3.5 hours after administration. 
     
     
       13. The solid dosage form of  claim 1 , wherein the time-release coating further comprises one or more of a buffering agent, alkalizing agent, or combination thereof. 
     
     
       14. The solid dosage form of  claim 1 , wherein the time-release coating further comprises one or more of an erosion regulator or diffusion regulator. 
     
     
       15. The solid dosage form of  claim 1 , wherein the time-release coating is applied onto the core as a solution or suspension. 
     
     
       16. The solid dosage form of  claim 1 , wherein the time-release coating is compressed onto the core. 
     
     
       17. The solid dosage form of  claim 1 , wherein the time-release coating slowly dissolves or disintegrates in aqueous media having a pH in the range of about 1.2-8.0. 
     
     
       18. The solid dosage form of  claim 1 , wherein the alkalizing agent is selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, a phosphate salt, alkaline silicate, talc, kaolin, Veegum, bentonite, alkaline electrolyte, alkaline nonelectrolyte, amino acid, alanine, bicarbonate salt, carbonate salt, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, alkaline amino acid, organic amine base, and trolamine. 
     
     
       19. The solid dosage form of  claim 1 , wherein the core comprises an inert nonpareil seed, pellet, or tablet onto which at least omeprazole and an alkalizing agent are sprayed prior to application of the time-release coating. 
     
     
       20. The solid dosage form of  claim 1 , wherein the time-release coating comprises one or more components selected from the group consisting of HPMC, HPC, PVP, ethylcellulose, non-enteric acrylic polymer, protein, talc, clay, kaolin, glycerin monostearate, wax, silicon dioxide, polysaccharide, polyethylene oxide, and alkaline buffering agent. 
     
     
       21. The solid dosage form of  claim 1 , wherein the dosage form further comprises one or more additional non-enteric coatings. 
     
     
       22. The solid dosage form of  claim 1 , wherein the core comprises a tablet, pellet or agglomerate consisting of an inert substrate onto which is sprayed a dispersion comprising omeprazole, a pharmaceutical binder and an optional alkalizing agent. 
     
     
       23. The solid dosage form of  claim 1 , wherein the time-release coating further comprises an alkalizing agent, antioxidant, preservative or a combination thereof. 
     
     
       24. The solid dosage form of  claim 1 , wherein the osmotic agent swells when contacted by the aqueous fluid in the environment of use to aid in the disintegration of the time-release coating. 
     
     
       25. The solid dosage form of  claim 2 , wherein the granule, bead, pellet, tablet, agglomerate, crystal, spheroid, microsphere, seed, microcapsule, or mini-tablet is included in a compressed tablet core. 
     
     
       26. The solid dosage form of  claim 1 , wherein the time-release coating delays the release of omeprazole from the core for a period of about 1.5-2.5 hours after administration. 
     
     
       27. The solid dosage form of  claim 1 , wherein the time-release coating delays the release of omeprazole from the core for a period of about 0.5-5.0 hours after administration. 
     
     
       28. A solid dosage form that provides a delayed and subsequently rapid release of omeprazole into an environment of use, wherein the dosage form comprises: 
       a core comprising omeprazole and at least one pharmaceutical excipient; and  
       a time-release non-enteric water soluble or water erodible coating surrounding and in contact with the core, wherein the time-release coating comprises one or more of an erosion regulator or diffusion regulator that regulate the strength, erosion property and/or diffusion property of the coating; the coating delays the contact of the core with a fluid in an environment of use for a period of at least one-half hour to delay the release of the omeprazole from the core; and the coating subsequently loses its physical integrity in an essentially pH independent manner after the delay period thereby permitting the core to rapidly release the omeprazole into the environment of use; and  
       wherein, the dosage form excludes an enteric release coating made from an enteric release polymer; the dosage form is adapted for oral administration; the time-release coating is sufficiently thick to retain its chemical and physical integrity in the stomach when administered orally; and the time-release coating loses its physical integrity in the upper portion of the GI tract downstream from the stomach of a subject to which the dosage form is administered.  
     
     
       29. The solid dosage form of  claim 28 , wherein the time-release coating delays the release of omeprazole from the core for a period of about 1-5.0 hours after administration. 
     
     
       30. The solid dosage form of  claim 29 , wherein the time-release coating is about 100-5000 microns thick. 
     
     
       31. The solid dosage form of  claim 29 , wherein the time-release coating slowly dissolves or disintegrates in aqueous media having a pH in the range of about 1.2-8.0. 
     
     
       32. The solid dosage form of  claim 29 , wherein the time-release coating further comprises one or more of a buffering agent, alkalizing agent, antioxidant, preservative or combination thereof. 
     
     
       33. The solid dosage form of  claim 29 , wherein the core further comprises one or more alkaline reacting compounds. 
     
     
       34. The solid dosage form of  claim 29 , wherein the core further comprises a disintegrant. 
     
     
       35. The solid dosage form of  claim 28 , wherein the time-release coating begins to erode shortly after administration to a patient and continues to erode for a period of at least 1 hour after which it loses its physical integrity and exposes the core to the environment of use thereby providing a delayed release of omeprazole. 
     
     
       36. The solid dosage form of  claim 28 , wherein the time-release coating does not erode initially, but permits the diffusion of an aqueous fluid therein and delays exposure of the core to the aqueous fluid for a period of at least 1 hour after which time the core rapidly disintegrates and the time-release coating loses its physical integrity. 
     
     
       37. The solid dosage form of  claim 28 , wherein the core comprises an inert nonpareil seed, pellet, or tablet Onto which at least omeprazole and an alkalizing agent are sprayed prior to application of the time-release coating. 
     
     
       38. The solid dosage form of  claim 28 , wherein the dosage form further comprises one or more additional non-enteric coatings. 
     
     
       39. The solid dosage form of  claim 28 , wherein the core comprises a tablet, pellet or agglomerate consisting of an inert substrate onto which is sprayed a dispersion comprising omeprazole, a pharmaceutical binder and an optional alkalizing agent. 
     
     
       40. A solid dosage form that provides a delayed and subsequently rapid release of omeprazole into an environment of use, wherein the dosage form comprises: 
       a core comprising omeprazole and at least one pharmaceutical excipient; and  
       a time-release non-enteric water soluble or water erodible coating surrounding and in contact with the core, wherein the time-release coating comprises one or more of an erosion regulator or diffusion regulator that regulate the strength, erosion property and/or diffusion property of the coating; the time-release coating is about 100-5000 microns thick; and the time-release coating loses its physical integrity in an essentially pH independent manner and delays release of the omeprazole from the core into an environment of use for a period of at least 0.5-3.5 hours after exposure of the dosage form to the environment of use; and  
       wherein, the dosage form excludes an enteric release coating made from an enteric release polymer; the dosage form is adapted for oral administration; the time-release coating is sufficiently thick to retain its chemical and physical integrity in the stomach when administered orally; and the time-release coating loses its physical integrity in the upper portion of the GI tract downstream from the stomach of a subject to which the dosage form is administered.  
     
     
       41. The solid dosage form of  claim 40 , wherein the time-release coating further comprises one or more of a buffering agent, alkalizing agent, antioxidant, preservative or combination thereof. 
     
     
       42. The solid dosage form of  claim 40 , wherein the time-release coating begins to erode shortly after administration to a patient and continues to erode for a period of at least 1 hour after which it loses its physical integrity and exposes the core to the environment of use thereby providing a delayed release of omeprazole. 
     
     
       43. The solid dosage form of  claim 40 , therein the time-release coating does not erode initially, but permits the diffusion of an aqueous fluid therein and delays exposure of the core to the aqueous fluid for a period of at least 1 hour after which time the core rapidly disintegrates and the time-release coating loses its physical integrity. 
     
     
       44. The solid dosage form of  claim 40 , wherein the core comprises an inert nonpareil seed, pellet, or tablet onto which at least omeprazole and an alkalizing agent are sprayed prior to application of the time-release coating. 
     
     
       45. The solid dosage form of  claim 40 , wherein the dosage form further comprises one or more additional non-enteric coatings. 
     
     
       46. The solid dosage form of  claim 40 , wherein the core further comprises one or more alkaline reacting compounds. 
     
     
       47. The solid dosage form of  claim 40 , wherein the core further comprises a disintegrant. 
     
     
       48. The solid dosage form is  claim 40 , wherein the core is a hard or soft capsule comprising a shell surrounding an omeprazole-containing composition, and the time-release coating surrounds the shell. 
     
     
       49. The solid dosage form is  claim 1 , wherein the core is a hard or soft capsule comprising a shell surrounding an omeprazole-containing composition, and the time-release coating surrounds the shell. 
     
     
       50. The solid dosage form is  claim 28 , wherein the core is a hard or soft capsule comprising a shell surrounding an omeprazole-containing composition, and the time-release coating surrounds the shell.